The proposal has the long term goal of determining the factors that cause sex differences in structure, function, and susceptibility to disease in mesencephalic dopamine systems. The studies will investigate the cellular and molecular mechanisms by which sex chromosome genes induce sex differences in phenotype of dopaminergic neurons in vivo and in vitro. Studies will determine whether the sex chromosome effect is due to genes on the X or Y chromosomes; whether steroid hormones of the Sry gene participate in the induction of sex differences; when during development the sex chromosome effect occurs; whether the sex chromosome effect is direct or indirect on dopamine neurons; the cellular mechanisms of the sex chromosome effect; and whether the sex chromosomes contribute to sex differences in the development and adult structure of the nigrostriatal dopamine system in vivo. The proposed studies will contribute to an understanding of the principles of sexual differentiation of the brain. At issue are the molecular mechanisms by which male and female brains differ, which is relevant to the biological basis of abnormalities of sexual differentiation, and to the explanation of sex differences in neurological and psychiatric disease, not only of those that affect dopamine systems (e.g., Parkinson's Disease, Tardive Dyskinesia, Tourette's Syndrome, schizophrenia), but other sexually dimorphic diseases as well. (e.g., Multiple Sclerosis). Understanding sex differences in brain function will help develop sex-specific strategies for treatment of brain diseases.